Education/Training Program Affiliations

Research Summary

Work in the Ellermeier Lab focuses on how two Gram positive bacteria, the model organism Bacillus subtilis and the opportunistic human pathogen Clostridium difficile, sense and respond to extracellular signals. We are particularly interested in understanding the response of C. difficile to factors produced by the innate immune system. We are interested in understanding how cells respond to changes in their environment by altering gene expression. To alter gene expression bacteria must detect changes in their environment and then transduce that signal from outside the cell to a transcriptional response inside the cell. We are interested in understanding the basic molecular mechanisms involved in how cells sense and respond to extracellular signals. We utilize genetic, molecular, biochemical and structural approaches to dissect these signal transduction systems.

Our work has revealed the presence of an Extra Cytoplasmic Function (ECF) σ factor, σV, present in B. subtilis and C. difficile that is activated specifically by lysozyme, an essential component of the innate immune system. We have found that σV is required for lysozyme resistance in both organisms. We have also found that σV is required for C. difficile to cause disease in an animal model of infection. The activity of σV is inhibited by the anti-sigma factor RsiV. Activation of σV occurs via proteolytic destruction of an anti-sigma factor RsiV. This degradation occurs only in the presence of lysozyme and requires multiple proteases to destroy RsiV in a process of regulated intramembrane proteolysis (RIP). We are interested in identifying the proteases required for σV activation and understanding the mechanism by which site-1 cleavage of RsiV, and thus σV activation, is controlled. We are also studying the role of additional ECF sigma factors encoded by C. difficile to determine their role in response to cell envelope stress. In addition we are interested in understanding the role of these ECF sigma factors play in survival of the bacterium during an infection.

A second area of focus for the laboratory is the process of cannibalism which occurs during B. subtilis sporulation. We are interested in understanding both the mechanisms of toxin production and how the senses and responds to the toxin SDP. Sporulation is initiated by the activation of a response regulator, Spo0A. The activity of Spo0A is not uniform across all cells of the population, in fact two subpopulations of B. subtilis exist, Spo0A-ON cells and Spo0A-OFF cells. The Spo0A-ON cells produce a toxin, SdpC, which is secreted and kills the SpoOA-OFF siblings. Normally, the Spo0A-ON cells resist the toxic effects of SDP by producing a membrane protein, SdpI, which provides immunity to the toxin. The immunity protein is only produced when extracellular toxin is present. Interestingly, SdpI is also required to induce its own expression in response to extracellular toxin sequestering a transcriptional repressor, SdpR, to the membrane. The sequestration of SdpR by the SdpC/SdpI complex inhibits the activity of the repressor thereby allowing increased transcription of sdpI, and immunity to the toxin.